William B. Klimstra and Kate D. Ryman
As reviewed elsewhere in this volume, the Alphavirus
genus of the family Togaviridae includes a number of important human and zoonotic pathogens that cause a variety of diseases, ranging from asymptomatic through mild, self-limiting febrile disease to polyarthritis/arthralgia (see chapter 7 for details of arthritogenic alphaviruses) or fatal encephalomyelitis (see chapter 8 for details of encephalitic alphaviruses), depending upon the virus. In traditionally used cell lines of murine or primate origin, however, wild-type alphaviruses tend to replicate rapidly. While the synthesis of virus proteins by host translation machinery is highly efficient, and thousands of progeny virions are released from each infected cell within 18-24 hours post-infection, host gene expression is almost completely arrested within a few hours via
independent inhibition of transcription and translation. Consequently, in vitro
the antiviral stress responses of the permissive host cell are very effectively suppressed by most, if not all, wild-type alphaviruses. In contrast, in vivo
the relative ability of each alphavirus to resist or evade inhibition by the type I interferon (IFN)-mediated antiviral response is arguably the most important factor determining virus virulence, and this can be reproduced to some degree in vitro
by using cell types relevant to the pathogenesis of each virus and maintaining the differentiated phenotype of such cells as completely as possible.
In this chapter, in order to understand the mechanisms involved in alphavirus virulence/attenuation, we will place in context recent findings about the interactions between the alphaviruses and the IFN-α/β system at the host, cellular and molecular levels. The current status of our knowledge in these areas is described in the following sections, focusing first from the host's perspective on IFN-α/β induction and effector mechanisms, and then on the mechanisms employed by the alphaviruses to inhibit, resist or avoid these responses read more ...